Industrial process for preparation of clopidogrel hydrogen sulphate

ABSTRACT

An improved process for the manufacture of Clopidogrel starting from 2-(2-thienyl)ethylamine, which eliminates the isolation of an unstable intermediate like 2-(2-thienyl)ethyl formimine by subjecting it to a one pot cyclization to get 4,5,6,7-tetrahydrothieno (3,2-c) pyridine of Formula II and further reacting with halo-compound of formula III (where X is Cl or Br) at 20 to 90° C. temperature characterized in a solvent like water and/or dichloroethane in presence of organic or inorganic bases is disclosed herein. This inventions also discloses Crystalline Form I of (+)-(S)-clopidogrel hydrogen sulphate and its preparation thereof.

The application is a divisional of U.S. patent application Ser. No.10/591,657, filed Sep. 5, 2006, the disclosure of which is incorporatedherein by reference.

TECHNICAL FIELD OF INVENTION

The present invention relates to an improved process for manufacturing(+)-(S)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4-H)-acetic acid methyl ester of Formula I, commonly known asClopidogrel starting from 2-(2-thienyl)ethylamine. The present inventionfurther relates to the process for resolution of the racemic clopidogrelinto its optical antipodes with high chiral purity. The presentinvention also provides a reproducible process for production ofhydrogen sulphate salt of clopidogrel in two crystalline forms viz:Form-I and Form-II.

BACKGROUND OF THE INVENTION

(+)-(S)-alpha-2-(chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4-H)-acetic acid methyl ester known as clopidogrel under theInternational Non-Proprietary Name is marketed as hydrogen sulphatesalt. Clopidogrel is known for its platelet aggregating andantithrombotic properties and finds medicinal applications in thisfield. It can be represented by Formula-I, and was disclosed in U.S.Pat. No. 4,529,596 (hereinafter referred as ‘596’ patent) in its racemicform for the first time.

The ‘596’ patent provides a synthesis of said molecule of Formula I bythe reaction of a thienopyridine derivative of Formula II with a chlorocompound of Formula III (where X═CI) in solvents like dimethylformamide, alcohols and ethyl acetate in presence of alkali metalcarbonates. However, it does not suggest preparation/source of thestarting material, tetrahyckothienopyridine derivative, of Formula II.

In a subsequent patent, JP 63101385, a convenient process for thepreparation of the 4,5,6,7-tetrahydrothieno (3,2-c) pyridineintermediate (Formula II) was disclosed. According to the multi-stepprocess of this patent, a commercially available2-(2-thienyl)-ethylamine (Formula IV) was reacted with formaldehyde togive an intermediate 1,3,5-tris-(2-thienylethyl)-hexahydro-S-triazinewhich was isolated and treated with HCl in polar solvents to give the4,5,6,7-tetrahydrothieno (3,2-c) pyridine of Formula II.

A similar process was disclosed in U.S. Pat. No. 5,132,435 for thepreparation of Clopidogrel by using the same reactants per se to yieldthe 4,5,6,7-tetrahydrothieno (3,2-c) pyridine derivative (Formula II)and reacting the same with a bromo-derivative of Formula III (X═Br) insolvents selected from alcoholic solvents, DMF, ether solvents and ethylacetate in presence of alkali metal carbonate as the base. In theprocess, 2-(2-thienyl)ethylamine was reacted with formalin solution inwater by heating to a temperature range of 70° C. to 90° C. and isolatedthe 2-(2-thienyl)-ethyl formimine by a long procedure in pure form. Thiswas reacted with dry hydrochloric acid solution in dimethylformamide toform the cyclized product (Formula II).

In these processes the reactants per se are same but employ varyingconditions to achieve better purity or yield. Although some of theproblems are solved by modifying the reaction conditions or route ofsynthesis as taught by the prior art, there still exist problems likepolymerization of intermediates which need to be investigated.

The cyclisation of the intermediate 2-(2-thienyl)-ethyl formimine doesnot take place in presence of water. If water is present in the reactionit necessitates the isolation of formimine intermediate in pure form.This increases the number of operations and makes process plantunfriendly from industrial scale-up point of view. Moreover, theisolated intermediate, 2-(2-thienyl)ethyl formimine, is not a stablecompound and polymerizes to give a trimer which makes it difficult tostore/handle in normal conditions.

Although, the reaction of bromo-compound (Formula III) with4,5,6,7-tetrahydrothieno (3,2-c) pyridine of Formula II gave moderateyields in the reported processes, the reactions takes long time forcompletion at temperature 60° C. to 90° C. as reported in ‘435’ patent.

Carrying out reactions at above temperatures, that too for longerperiod, lead to formation of various impurities due to the lack ofselectivity of reactions or decomposition of the reactants or products,which necessitates extra purification resulting into yield losses andincrease in number of operations not desirable for a practical process.The search for a manufacturing process for the preparation ofClopidogrel employing easy synthetic methods resulting in a satisfactoryyield/purity of final product remains undoubtedly of interest.

The pure enantiomeric forms of clopidogrel (dextro and levo isomers) wasdisclosed in EP 281459 which teaches the isolation of the dextrorotatory isomer of Clopidogrel by diasteriomeric salt formation ofracemic Clopidogrel base using an optically active acid such as10-L-camphor sulfonic acid in solvents like acetone, followed bysuccessive recrystallization of the salt until a product with constantrotatory power was obtained. The pure dextrorotatory isomer ofclopidogrel (herein after referred as clopidogrel free base) wasreleased from the respective diasteriomeric salt by reaction with abase.

But in practice, the diasteriomeric salt that separates out wasfiltered, and purified by refluxing, cooling and filtration from acetoneresults in low yield of the dextro isomer (55%). The process ofpurification in acetone is repeated several times for obtaining thedesired purity of diasteriomeric salt. The chiral purity of thedextroisomer is low (96%) even after the repeated crystallization.

The Clopidogrel free base was then converted into its hydrogen sulfatesalt by dissolving in acetone, cooling and mixing with concentratedsulfuric acid to precipitation. The precipitate thus obtained is thenisolated by filtration, washed and dried to give Clopidogrel hydrogensulfate in the form of white crystals whose melting point was 184° C.and optical rotation was +55.1° (c=1.891/CH3OH). But '459 patent did notcharacterize or suggest any name to this crystals (polymorph) ofClopidogrel hydrogen sulfate.

Subsequently International patent publication, WO 99/65915 (herein afterreferred as '915 patent), disclosed two polymorph forms of Clopidogrelhydrogen sulfate referred to as Form-I and Form-II. The '915 patentidentified that the precipitation method described in '459 patent hadled to crystalline Form-I. The '915 also deals with a new crystallineform called Form-II of Clopidogrel hydrogen sulfate. The latter issuggested to be thermodynamically most stable crystalline form.According to '915 patent both polymorphs, namely Form I and Form II,were prepared from the same solvent viz; acetone.

The process for obtaining crystalline Form-II of Clopidogrel hydrogensulfate according to example 1A of the '915 patent describes theintroduction of Clopidogrel camphor sulfate in MDC and transformation ofsalt into the base with potassium carbonate solution. Clopidogrel baseis extracted in MDC and evaporated. Residue obtained is dissolved inacetone and cooled. Addition of sulfuric acid precipitated outClopidogrel hydrogen sulfate. Also in the same application it wasdescribed to get Form-II either by keeping mother liquor of Form-I or byheating acetone solution containing the base after addition of sulfuricacid to reflux or by subjecting the suspension to mechanical shearingusing a shearing device or by inoculation.

However, this process was not suitable for the production of Form I ofclopidogrel hydrogen sulphate on an industrial scale owing to itsthermodynamic instability in solvents like acetone and invariablyyielded Form II without having the need of keeping for longer periods(ref. '915 patent). This problem became the subject of the patentapplication WO 2004020443 (herein after referred as '443 patent).

According to the '443 patent application, a process was claimed toproduce Form I consistently by forming hydrogen sulphate salt ofclopidogrel from a solvent selected from the series of CL-C₅ alcohols ortheir esters with CL-C₄ acids, optionally of mixture of alcohols andesters. The process involves dissolving clopidogrel base in solventslike isopropyl alcohol and/or butyl acetate, cooling the mixture, addingsulfuric acid and inoculating the mixture with Form-I of Clopidogrelhydrogen sulfate. Stirring the crystallized mixture precisely at atemperature between −5 and +15° C. to get crystals of clopidogrel inForm-I. In another process variant, the subject of '443 patent, theclopidogrel hydrogen sulphate was directly dissolved at reflux in theabove mentioned solvents and crystallized under cooling.

Although the process mentioned in the '443 patent application works inbutyl acetate, which is known to have hazardous properties (affectscentral nervous system and exposure limit is 150 ppm), but fails to givepure Form I in other industrially friendly solvents like ethyl acetateunder the specified conditions. As the Form I is thermodynamicallyunstable, the process variant of dissolving clopidogrel hydrogensulphate salt in solvents at higher temperature and cooling toprecipitate Form I resulted in Form II or Form IV or their mixture withForm I.

This finding is in agreement with the prior art disclosed in UnitedStates patent application 2003/0225129 A₂ (herein after referred as '129patent), where isopropanol was used to produce Form-IV crystals (Form IVof clopidogrel hydrogen sulphate is known to be its isopropyl alcoholsolvate) by a process comprising the steps of preparing solution ofClopidogrel hydrogen sulfate either by using Clopidogrel base or itshydrogen sulfate salt in isopropyl alcohol at reflux and cooling toprecipitate Clopidogrel hydrogen sulfate and separating the mentionedpolymorph, i.e. Form IV.

The '129 patent also describes process for the preparation of Form-IIfrom solvents selected from dichloromethane, 1,4-dioxane, toluene,chloroform, ethyl acetate, methyl ethyl ketone and t-butyl methyl ether.The '129 patent, for the first time, claimed to produce Form II fromethyl acetate which was the main subject of '443 patent application.

Moreover, in our hands under the specified conditions at lowertemperature of −5° to 15° C., as claimed in the '443 patent, we foundthe crystals formed in ethyl acetate is Form II of clopidogrel hydrogensulphate.

It is clear from above discussion that same solvent gives two differentcrystalline forms under different experimental conditions.

So, it is evident from the prior art that methods to produce Form-I ofclopidogrel hydrogen sulphate from different solvents are poorlyreproducible, necessitating the optimization of experimental conditionsother than of the selection of solvents. Since Form-I is kineticallycontrolled and Form-II is thermodynamically controlled form, theyrequire very specific temperature range and specific conditions forgetting reproducible results. Also, a minor variation in conditionappears to give Form-II instead of expected Form-I or a mixture ofForm-I & Form-II. Since, Form I of clopidogrel hydrogen sulphate is usedfor pharmaceutical formulation, the importance of a rugged method thatgives Form I consistently doesn't require any emphasis.

Apart from the inconsistency of the process in solvents like ethylacetate, the process given in the '443 patent application also suffersfrom operational problems from an industrial scale-up point of view asfollows;

During the salt formation in solvents like ethyl acetate at lowertemperature, the product forms a sticky & lumpy mass that sticks to thestirrer and difficult to disperse due to the lowered solubility at thiscondition,

The workability of the process found limit to single solvent mainlybutyl acetate which is a hazardous and industrially unfriendly,

The crystal form obtained by performing the salt formation between 5° to15° C. in ethyl acetate is Form II of clopidogrel hydrogen sulphate.This may be due to the non-dispersability of the sticky mass obtainedunder these conditions and the fast/prolonged stiffing performed fordispersion, allows the crystals to grow and rearranges to the moststable form.

Thus there is a need to get industrially reliable process for thepreparation of Form-I and Form-II without contamination of one intoother Form. So it was of interest to find a suitable solvent where thecrystallization can be performed at a temperature near to ambienttemperature, for solving the inconsistency/operational problems in theprior art, yielding clopidogrel Form I in its pure state. Also ofinterest was to see its workability at higher temperature to affect afast and easily dispersible crystallization conditions, an importantfactor for operations.

OBJECTIVES OF THE PRESENT INVENTION

It is, therefore, an objective of the present invention to provide anindustrially useful process for the manufacture of Clopidogrel fromstarting materials that are readily and commercially available,relatively inexpensive, and easily maneuvered at large scale operations.

Other objectives of this invention are:

To provide a single pot conversion process for unstable intermediate2-(2-thienyl)ethyl formimine formed in the reaction to a stable productof Formula II.

To design a process for preparation of Clopidogrel wherein thecondensation of halo ester with 4,5,6,7-tetrahydrothieno (3,2-c)pyridine is performed under ambient conditions with accelerated rate ofreaction.

To provide, optionally, a one-pot processes for the preparation ofracemic Clopidogrel starting from 2-(2-thienyl)ethylamine.

To provide suitable solvents for resolving racemic clopidogrel base intosubstantially pure enantiomers in a single diasteriomeric fractionalseparation step in higher outputs.

A further objective of the present invention was to find solvent systemswhere the Form I crystals of clopidogrel hydrogen sulphate can beefficiently and reproducibly formed on industrial scale. Theseobjectives become the subject of the present invention.

SUMMARY OF THE INVENTION

Accordingly, in a first aspect, there is provided an improved processfor the manufacture of Clopidogrel starting from2-(2-thienyl)ethylamine, which eliminates the isolation of an unstableintermediate like 2-(2-thienyl)ethyl formimine by subjecting it to a onepot cyclization to get 4,5,6,7-tetrahydrothieno (3,2-c) pyridine ofFormula II.

In one embodiment of the present invention, the 4,5,6,7-tetrahydrothieno(3,2-c) pyridine is reacted with halo-compound of Formula III (where Xis Cl or Br) at room temperature in a solvent like water and/or ethylenedichloride (EDC) in presence of organic or inorganic bases like sodiumcarbonate.

In preferred embodiment of the invention, the 2-(2-thienyl)ethylamine isreacted with paraformaldehyde in solvents such as hydrocarbon solventsincluding aliphatic, aromatic and chlorinated hydrocarbon solvents andremoving the water formed, azeotropically during reaction. The2-(2-thienyl)ethyl formimine solution is cyclized in a single pot bysupplying dry HCl gas/solution.

In yet another embodiment, the reaction of Formula II with Formula IIIis carried out in a combination of solvents like water and chlorinatedhydrocarbon solvents at room temperature.

In yet another embodiment, the production of Clopidogrel is carried outin a single pot by reacting 2-(2-thienyl)ethylamine withparaformaldehyde in organic solvents, azeotropically removing waterformed in the reactor, cyclizing the 2-(2-thienyl)ethyl formimine bysupplying dry HCl gas/solution, and reacting the4,5,6,7-tetrahydrothieno (3,2-c) pyridine formed with a solution ofhaloester (Formula III, where X═Cl or Br) in water or organic solvent ortheir mixtures thereof in presence of a base.

In a second aspect of the present invention, a racemic resolution of(±)methyl2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetateto get substantially pure dextro rotatory enantiomermethyl-(S)-(+)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetate (Formula IA) using anhydrous levo-camphor-10-sulphonic acid in amixture of solvents selected from combination of polar andnon-polar/weakly polar solvents like acetone: dichloromethane, acetone:toluene, and acetone: cyclohexane is provided.

In a third aspect, the present invention provides an improved industrialprocess for crystallizing out polymorph ‘Form I’ of (+) clopidogrelhydrogen sulphate (also called clopidogrel hydrogen sulphate) insolvents such as methyl propyl ketone, methyl isopropyl ketone, diethylketone or their mixture thereof, ethyl acetate, mixture of ethyl acetateand methyl propyl ketone, mixture of ethyl acetate and methyl isopropylketone, mixture of ethyl acetate and diethyl ketone, in a reproduciblemanner without detectable contamination of ‘Form II’.

In a preferred embodiment of the present invention the process for ‘FormI’ comprises dissolving the clopidogrel base in solvent such as methylpropyl ketone or methyl isopropyl ketone or diethyl ketone or mixture ofethyl acetate and methyl propyl ketone or mixture of ethyl acetate andmethyl isopropyl ketone, mixture of ethyl acetate and diethyl ketone atroom temperature (20 to 30° C.), then cooling the obtained clopidogrelbase solution to a temperature of −10 to 10° C., adding concentratedsulphonic acid (98%, d=1.84) while maintaining the temperature in therange −10 to 20° C., further maintaining the temperature at about 10 to30° C. for about 12 to 17 hours and filtering the crystals of Form Iobtained.

In another embodiment, present invention provides a process for ‘Form I’clopidogrel hydrogen sulphate in ethyl acetate, in a reproducible mannerwithout detectable contamination of Form-II at a temperature rangingfrom 18° to 30° C. in a duration of 8 to 10 hours. The present inventionalso provides process for the formation of clopidogrel Form II fromethyl acetate at a temperature of 45° C. to 50° C. without detectablecontamination of Form I.

The present invention provides process for preparation of both Form-Iand Form-II from the same solvent, i.e. ethyl acetate, at differentexperimental condition, which gives operation-wise flexibility andexcellent reproducibility, making the process practical and plantfriendly.

In a further embodiment, the present invention provides a process forthe preparation of ‘Form II’ clopidogrel hydrogen sulphate from acommonly used solvent like isopropanol and tetrahydrofuran.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 represents Powder X-Ray diffraction pattern (PXRD) of clopidogrelhydrogen sulphate Form I prepared according to example 7 of the presentinvention.

FIG. 2 represents Powder X-Ray diffraction pattern (PXRD) of clopidogrelhydrogen sulphate Form II prepared according to example 10 of thepresent invention.

FIG. 3 represents Differential Scanning Calorimetry record of Form I ofclopidogrel hydrogen sulphate prepared according to example 7 of thepresent invention.

FIG. 4 represents Differential Scanning Calorimetry record of Form II ofclopidogrel hydrogen sulphate prepared according to example 10 of thepresent invention.

FIG. 5 represents Powder X-Ray diffraction pattern (PXRD) of clopidogrelhydrogen sulphate Form I standard as given in '915 patent.

FIG. 6 represents the spectrogram obtained by Fourier Transform InfraRed spectrometry (FTIR) of clopidogrel hydrogen sulphate Form I preparedaccording to example 7 of the present invention.

FIG. 7 represents spectrogram obtained by Fourier Transform Infra Redspectrometry (FTIR) of clopidogrel hydrogen sulphate Form II preparedaccording to example 10 of the present invention.

FIG. 8 represents an overlay of powder x-ray diffraction pattern (PXRD)of clopidogrel hydrogen sulphate crystalline Form I and Form II.

DETAILED DESCRIPTION OF THE INVENTION

The improved process for preparation of racemic clopidogrel, itsresolution, and conversion to hydrogen sulphate salt in specificcrystalline forms viz; ‘Form I’ and ‘Form II’ are described in detailwith the specific embodiments/conditions here after.

It has now been found that new condition/process makes it possible toconvert 2-(2-thienyl)ethylamine to 4,5,6,7-tetrahydrothieno (3,2-c)pyridine via 2-(2-thienyl)ethyl formimine in a single step in one-potand thereby eliminating the isolation of unstable intermediate,2-(2-thienyl)ethyl formimine, making the process industrially morefeasible.

Consequently, the invention relates to an improved synthesis ofClopidogrel by reacting 2-(2-thienyl)ethylamine with paraformaldehyde inpresence of dry HCl, optionally isolating the compound of Formula II,and reacting with halo-compound of Formula III (X═Cl or Br) in a singleorganic solvent or a combination of organic solvents and water.

Accordingly, the 2-(2-thienyl)ethylamine is reacted withparaformaldehyde in a suitable solvent selected from non-polar solventlike aliphatic and aromatic hydrocarbon solvents, chlorinatedhydrocarbons like dichloroethane (EDC) etc. The reaction takes place ata temperature of 30° C. to 100° C. and the water formed as a byproductin the reaction is removed continuously by azeotropic distillation usinga Dean-Stark assembly or the like. Azeotropic distillation herein meansremoval of two or more solvents from a mixture of solvents that form alow boiling mixture called azeotrope by distillation at elevatedtemperature.

After removal of water, the intermediate 2-(2-thienyl)ethyl formimineformed in solution is in situ reacted with dry HCL gas. The dry HCL alsocan be advantageously introduced into reactor as a solution in asuitable organic solvent. The solvent used for this purpose includedimethyl formamide, alcoholic solvents like methanol, ethanol, isopropylalcohol etc. The one pot conversion of 2-(2-thienyl)ethylamine takesplace in a period of 4 to 8 hours. The preferred temperature forcarrying out the cyclization of intermediate in presence of the acidcatalyst is in the range from 60° C. to 90° C.

According to present invention, the cyclization of 2-(2-thienyl)ethylformimine obtained takes place in-situ spontaneously in presence of acidand yields the stable intermediate 4,5,6,7-tetrahydrothieno (3,2-c)pyridine as its hydrochloride salt. The said salt precipitates from thereaction medium and conveniently isolated in substantially pure form.

The acid catalyzed cyclization of 2-(2-thienyl)ethyl formimine ispreferably carried out at a temperature range of 70° C. to 75° C., for aperiod of 4 hours.

According to a preferred embodiment of the invention, the4,5,6,7-tetrahydrothieno (3,2-c) pyridine as a free base or itshydrochloride salt form is reacted with a halo derivative of Formula IIIin organic solvent especially dichloroethane in presence of an organicbase to obtain Clopidogrel. The organic base for carrying out this stepof the process is selected from the group consisting of trialkyl aminessuch as triethylamine, trimethylamine, diisopropylethylamine and thelike. The preferred base is triethylamine. The preferred halo derivativeof Formula III is the bromo compound (Formula III, where X═Br).

According to the above process step of the present invention, whereinthe compound III and 4,5,6,7-tetrahydrothieno (3,2-c) pyridine isreacted, the reaction is carried out at a temperature range of about 50°C. to about 80° C. for about 4 to 4.5 hours, preferably about 3.5 hoursat 70° C. In this step of the process, where the acid salt of Formula IIis used as reactant, then an excess amount of the base is used. This isrequired to neutralize the acid salt to liberate the free base of thecompound of Formula II that reacts with the halo derivatives of FormulaIII.

In another embodiment of the invention, the process step of reaction of4,5,6,7-tetrahydrothieno (3,2-c)pyridine with the halo compound ofFormula III is carried out in a heterogeneous mixture of solventsselected from a combination of water and chlorinated hydrocarbonsolvents such as dichloromethane or dichloroethane. The preferredsolvent is a mixture of water and dichloroethane. The preferred ratio ofwater and dichloroethane is 1:0.5. A specific advantage of this reactionmedium is that a phase-transfer catalyst as taught by prior patents isnot required and the reaction can be performed at ambient conditions.

The base for carrying out the above process step is selected from thegroup consisting of inorganic bases like alkali metal carbonates. Thepreferred alkali metal carbonate used is sodium carbonate or potassiumcarbonate.

Preferably the inorganic base may be used in molar equivalent ratiorelative to the halo compound of Formula III or in slight excess. In thecase of reaction of acid salt of Formula II with Formula III, an excessbase is used to liberate the free amine from acid salt. A preferableratio of base used in this case ranges from 2 moles to 3 moles relativeto compound of Formula II.

In this step of the process, the 4,5,6,7-tetrahydrothieno(3,2-c)pyridineor its hydrochloride salt and the inorganic base is preferably taken inwater in a reaction vessel. The addition of a compound of Formula III iscarried out as its solution in dichloroethane to form the heterogeneousreaction conditions. This process is particularly advantageous from thepoint of view of handling the halo compound of Formula III, due to itshighly irritant and lachrymator properties.

According to the process of the present invention, this step isadvantageously carried out at ambient temperature. Although the reactiongoes faster at high temperature, to limit the impurity generation, thisstep is carried out at a temperature of 25° C. to 30° C. for a period of7 to 10 hours, preferably 10 hours.

The Clopidogrel prepared following the above method is isolated by phaseseparation and washing the organic layer with water. The organic layeris removed by evaporation and the clopidogrel base obtained is purifiedin acetone by making its hydrogen sulphate salt. The pure Clopidogrelhydrogen sulphate is isolated as pure crystals from the solvent bysuction filtration and drying.

According to a particularly advantageous alternative form of the presentinvention, the preparation of Clopidogrel may be carried out from4,5,6,7-tetrahydrothieno (3,2-c) pyridine intermediate in the actualmedium (hydrocarbon solvents) in which it is prepared in a single pot.

Consequently, according to the invention, clopidogrel is prepared by thefollowing reactions in a single pot.

2-(2-thienyl)ethylamine is reacted with paraformaldehyde in suitablesolvent as described earlier and removing the water formed in thereaction azeotropically.

Introducing dry HCL in the form of solution or gas and cyclizing thecorresponding formimine to give 4,5,6,7-tetrahydrothieno(3,2-c)pyridineas hydrochloride salt in the reaction vessel,

Saponifying the hydrochloride salt of4,5,6,7-tetrahydrothieno(3,2-c)pyridine of Formula II with introductionof an aqueous solution of sodium or potassium carbonate in requiredamounts,

Introducing halo-compound of Formula III as such or as a solution inorganic solvent used for the stage 1 and reacting at a temperature of25° C. to 30° C. for a period of 8 to 10 hours, preferably 10 hours,

Isolating the Clopidogrel base in the organic layer after phaseseparation and washing with water, removing the solvent” by evaporationto leave Clopidogrel base as residue in the reaction vessel, and

Isolating pure Clopidogrel hydrogen sulphate by introducing acetone andcone, sulphuric acid into the reaction vessel.

The addition of Sulphuric acid is carried out preferably at atemperature of 0° C. to 25° and the addition of Sulphuric acid to theacetone solution of Clopidogrel base may be carried out in a controlledmanner so as to avoid undue exothermicity with proper cooling. Thehydrogen sulphate salt was further treated with a base like sodium orpotassium carbonate to liberate the free clopidogrel base.

The Clopidogrel base obtained by the process of the present inventionis, further, resolved into its enantiomers using optically activecamphorsulphonic acid. The process of resolution involves contactingClopidogrel base with (−) camphor sulphonic acid in a mixture of polarand non-polar/weakly polar organic solvents and crystallizing thedextroisomer as a diasteriomeric salt of camphor sulphonic salt.

The solvent of choice used in preparing combination solvents is selectedfrom acetone, dichloromethane, toluene and cyclohexane. The mixtures ofsolvents ideal for resolution of racemic clopidogrel are combination ofacetone: dichloromethane, acetone: toluene, and acetone:cyclohexane;wherein the preferred mixtures of the solvents are combination ofacetone:dichloromethane and acetone:toluene, and the most preferredmixture of the solvents is acetone:dichloromethane. This solventcombination in a preferred proportion is essential for the success ofresolution in respect of yield and purity in a single crystallizationstep. The preferred ratio of the solvents used is 20:0.5 (10:0.25),wherein the more preferred ratio is 15:0.75 and the most preferred ratiois 10:1. It is preferable to use anhydrous levo-camphor-10-sulphonicacid and the most preferred molar ratio of camphor sulphonic acid is1.05 to 1.1 molar equivalents relative to the racemic clopidogrelmixture. The salt formation is carried out in the temperature range of25-35° C., preferably at 30±2° C.

The diasteriomer salt is then hydrolyzed using alkali metal carbonatessuch as sodium carbonate or ammonia to liberate the dextro enantiomer ofClopidogrel as free base. After hydrolysis, (+)(S) Clopidogrel base wasisolated by extraction using organic solvents like dichloromethanefollowed by evaporation of solvent to give (+) Clopidogrel having anenantiomeric purity more than 99.5% with an yield of 76 to 80%.

Owing to the economy of the process, the unwanted isomer, (−)(R)clopidogrel camphor sulphonate salt, left behind in the mother liquorafter crystallization of S-isomer is racemized and recycled. The motherliquor containing (−)(R) clopidogrel camphor sulphonate along with someamount of unrecovered S-isomer after removal of crystallization solventis treated with NaOH in alcoholic solvents like methanol at atemperature ranging from 30 to 50° C. to obtain a 50:50 ratio of bothisomers (referred as racemic mixture). After racemization, the (±)clopidogrel free base is isolated by solvent evaporation, and extractionusing a mixture of dichloromethane and water. The dichloromethane layercontains the (±) clopidogrel base and aqueous layer contains theresolving agent (camphor sulphonic acid) and both are recovered andrecycled. A particularly important aspect of this process of inventionis that it avoids the isolation of (R) clopidogrel base from thediasteriomeric salt and directly converts it to the (±) clopidogrelbase.

Finally, the dextro clopidogrel free base obtained above is converted tohydrogen sulphate salt in its two crystalline polymorphs, ‘Form I’ and‘Form II’ by a reproducible process on large scale.

Large scale production of these two crystalline Forms according to theprocess described in the '915 patent resulted in Form II or a mixture orcontaminated with either form at a higher percentage. Also the improvedprocess of '443 patent application resulted in scale-up problems onlarge scale due to lump formation and semi-solid/sticky nature of theproduct at lower temperature and converts to more stable ‘Form II’. Alsoencountered problems in maintaining precise control of temperature atdifferent set points as stated in the '443 patent on large scaleproduction.

This lead us to find suitable solvents or conditions where theseproblems are minimized and ensure reproducibility of Form I and II,particularly Form I without contamination of other forms. This researchhas led to an efficient process where Form I and Form II can be producedreliably from a single solvent or mixture of solvents.

Accordingly, the present invention provides a process for preparingpolymorph Form I of clopidogrel hydrogen sulphate comprising dissolvingthe (±) clopidogrel base in solvents like methyl propyl ketone, methylisopropyl ketone, diethyl ketone or mixture thereof, or mixture of ethylacetate and methyl propyl ketone or mixture of ethyl acetate and methylisopropyl ketone, or mixture of ethyl acetate and diethyl ketone;cooling to a temperature of −10° C. to 10° C.; adding concentratedsulphuric acid (98%, d=1.84) by maintaining the temperature at in therange of −10 to 20° C.; raising to a temperature of 10° C. to 15° C. andmaintaining for 5 to 7 hours; further raising to a temperature of 28° to30° C. and maintaining for a period of 7 to 10 hours and filtering thecrystals obtained.

The mixture of ketone solvents include mixture of methyl propyl ketoneand methyl isopropyl ketone, mixture of methyl propyl ketone and diethylketone, mixture of methyl isopropyl ketone and diethyl ketone, in allproportions.

In a further embodiment, the present invention provides a process forpreparing polymorph Form I of clopidogrel hydrogen sulphate from ethylacetate comprising the steps of dissolving the (+) clopidogrel base inethyl acetate, cooling to a temperature of 18° C., adding concentratedsulphuric acid with or without maintaining temperature at 18°, raisingto a temperature of 28° to 30° C. and maintaining for a period of 7 to10 hours and filtering the crystals obtained.

In the process, in ethyl acetate, the temperature range of 18° to 30° C.gave Form I reproducibly on a large scale. Within this temperature rangean easily dispersible mass is obtained and slight imbalance oftemperature is well tolerated to give Form I consistently.

In both the cases, in the process for Form I, the preferredconcentration of sulphuric acid was in the range of 90% to 98% and themolar ratios were in the range of 1 to 1.1 with respect to the (+)clopidogrel base. The most preferred concentration of sulphuric acidused in the salt formation was 96%.

In a preferred embodiment of the process, the exotherm of sulphuric acidaddition is controlled by cooling and maintaining the temperature inbetween 18° to 24° C. in case of solvent ethyl acetate; and cooling andmaintaining the temperature in between −10 to 10° C. in case of solventsmethyl propyl ketone, methyl isopropyl ketone, diethyl ketone or theirmixture thereof, or mixture of ethyl acetate and methyl propyl ketone ormixture of ethyl acetate and methyl isopropyl ketone, or mixture ofethyl acetate and diethyl ketone.

The Form I so obtained was confirmed by PXRD, DSC and FTIR without anydetectable quantity of Form II or other polymorphic Forms with respectto the standard Form I PXRD pattern as described in '915 patent.

In another aspect, Form II crystals of (+) clopidogrel hydrogen sulphateis prepared from the same solvent ethyl acetate comprising steps ofdissolving (+) clopidogrel base in the solvent, heating to a temperatureof 45° C., adding concentrated sulphuric acid, stirring the reactionmixture at 45° C. to 50° C. for a period of 1 hour, cooling to 30° C.and continue stiffing for a period of 4 to 7 hours to effect thecomplete crystallization.

In the process, the preferred concentration of sulphuric acid was in therange of 90% to 98% and the molar ratios were in the range of 1.0 to 1.1with respect to clopidogrel base. The most preferred concentration ofsulphuric acid used in the salt formation was 96%.

The Form II obtained by the process of the invention was confirmed byPXRD, DSC and FTIR and found to be identical with it disclosed in the'915 patent without any detectable contamination of Form I.

In yet another aspect, Form II of clopidogrel is prepared from ethylacetate at a lower temperature of 5° to 15° C. comprising the steps ofdissolving (+) clopidogrel base in ethyl acetate at 25° to 30° C., coolto 5° to 15° C. and mixing with conc. sulphuric acid at the saidtemperature, maintaining the mass under stiffing for a period of 8 to 10hours at 5 to 15° C. to yield crystals of clopidogrel Form II. Thecrystals obtained are filtered and dried and is identified as Form II byPXRD, FTIR and DSC without detectable contamination of Form I.

To our surprise the crystal form obtained at temperature below 15° C.and above 40° C. process conditions are the stable Form II crystals,while the temperature range of 18° to 30° C. processing conditionsinvariably yielded crystal Form I of clopidogrel hydrogen sulphate.

In another embodiment, the present invention provides a process, for thepreparation of Form II crystals of clopidogrel hydrogen sulphate fromisopropyl alcohol comprising steps of dissolving clopidogrel base insolvent, adding concentrated sulphuric acid at a temperature of 28° to30° C., stirring to effect complete crystallization for a period of 12to 15 hours, filter and dry the crystals. The crystal form is identifiedequivalent to Form II. This solvent system (isopropyl alcohol) is,however, known to give Form IV.

In a preferred embodiment of the process the concentrated sulphuric acidis added as a solution in isopropyl alcohol.

The present invention also provides a process for the preparation ofForm II of clopidogrel hydrogen sulphate from tetrahydrofuran comprisingsteps of dissolving clopidogrel base in solvent, cooling the reactionmass to a temperature of 10° to 15° C.; adding concentrated sulphuricacid at a temperature of 10° to 15° C., stiffing to effect completecrystallization for a period of 6 to 8 hours, filter and dry thecrystals. The crystal form is identified equivalent to Form II.

The following examples further illustrate the present invention but arenot construed limiting in any manner to the scope of the invention assubstantially described.

EXAMPLES Example 1

One pot process for 4,5,6,7-tetrahydrothieno[3,2-c]pyridinehydrochloride 100 gm. of 2-thienylethylamine was charged in a 1 litrereaction vessel equipped with a dean stark assembly for azeotropicremoval of water. Dichloroethane (600 ml.) was added and the mixturestirred for 5 minutes. 26.4 gm. paraformaldehyde was added and thereaction mass was heated to reflux. Water formed in the reaction wascontinuously removed. After 4 hours the reaction mass was cooled to 30°C. and 133 ml. of 6.6N hydrochloric acid solution in dimethyl formamidewas added. The reaction mass was heated to 70° C. for 4 hours. Thereaction cooled to 15° C. and filtered under suction and washed withdichloroethane. The solid obtained was dried in oven at 50° C. 124 gm.(90%) of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride areobtained.

Example 2

Clopidogrel base and clopidogrel hydrogen sulphate (dichloroethane assolvent). 50 gm. 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloridewas charged in 1 litre reaction vessel. 150 ml. dichloroethane was addedand stirred for 5 minutes. 75 gm. ofmethyl-1-bromo-(2-chlorophenyl)acetate and 80 ml. triethyl amine wasadded. Stirred at 25° C. for 1 hour and then heated to reflux for 4hours. The reaction mixture cooled to room temperature and quenched inwater. The organic layer was washed with water, and distilled thedichloroethane to obtain clopidogrel base as an oil.

This clopidogrel base was dissolved in 300 ml. acetone and mixed with17.5 ml. Conc. Sulphuric acid under cooling. The precipitated pureClopidogrel hydrogen sulphate was filtered and washed with acetone. Theprecipitate was dried in an oven at 50° C. and 105 gm. (88%) Clopidogrelhydrogen sulphate was obtained.

Example 3 Clopidogrel Base and Clopidogrel Hydrogen Sulphate (Water andDichloroethane as Reaction Medium)

50 gm. of 4,5s637-tetrahydrothieno[3,2-c]pyridine hydrochloride wascharged in 1 litre reaction vessel containing 500 ml. water and 75.4 gm.sodium carbonate and stirred for 1 hour. 75 gm. ofmethyl-1-bromo-(2-chlorophenyl)acetate in 250 ml. dichloroethane wasadded, stirred at 25° C. for 8 hours. The organic layer was separatedand washed with water, and distilled the dichloroethane to obtainClopidogrel base as an oil.

This was dissolved in acetone (300 ml.), cooled to 0-5° C. and mixedwith 17.5 ml. conc. Sulphuric acid under cooling. The precipitated pureClopidogrel hydrogen sulphate was filtered and washed with acetone. Theprecipitate was dried in an oven at 50° C. The 105 gm. (88%) Clopidogrelhydrogen sulphate was obtained.

Example 4 One-Pot Process for Clopidogrel Hydrogen Sulphate fromThienoethylamine

100 gm. of 2(2-thienyl)ethylamine was charged in a reaction vesselequipped with a dean-stark assembly for azeotropic removal of water.Dichloroethane (600 ml.) was added and the mixture stirred for 5minutes. 26.4 gm. paraformaldehyde was added and the reaction mass washeated to reflux. Water formed in the reaction was continuously removedin 4 hours. The reaction mass was cooled to 30° C. and 133 ml. of 6.6 Nhydrochloric acid solution in dimethyl formamide was added. The reactionmass was heated at 70° C. for 4 hours. The reaction cooled to 25° C. andan aqueous solution of sodium carbonate (prepared from 1400 ml. waterand 208 gms sodium carbonate) was added. The mixture was stirred for 1hour and a solution of 206.7 gm. ofmethyl-1-bromo-(2-chlorophenyl)acetate in 690 ml. dichloroethane wasadded. The reaction mass stirred at room temperature for 9 hours and theaqueous layer is discarded. The organic layer washed with water anddichloroethane was evaporated. To the oil left in the reaction vessel,825 ml. acetone was added and stirred for 1 hour. The mass cooled to 0to 5° C. and 48 ml. conc. Sulphuric acid was added. The mixture wasfurther stirred for 4 hours. The precipitated crystals filtered offunder suction and the pure Clopidogrel hydrogen sulphate was dried inoven at 50° C. to get 280.5 gm (85%).

Example 5 (S)(+) Clopidogrel Base

93.0 gm (0.28 mole) of racemic basemethyl-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetatewas charged in 550 ml. mixture, of acetone and dichloromethane solvent.73.8 gm (0.31 mole) levo-camphor-10-sulphonic acid was added in thesolution. The clear solution was stirred overnight at 30±2° C. andcooled the reaction mass to −2 to 3° C. The crystals obtained wasfiltered and washed with acetone and dried at room temperature undervacuum to give 61 gm of diastereomeric salt of (S)clopidogrel. The yieldobtained is 76.0% on the basis of the starting racemate charged. Thecrystals have |a|_(D) ²⁰+25.25 (c=1.89%, methanol); HPLC (AGP_((R))column) assay=99.65%.

The diasteriomeric salt (60 gm) obtained above was dissolved in 240 ml.water containing 16.8 gms of Sodium bicarbonate and 240 ml. ethylacetate was added and stirred for a period of 2 hours at roomtemperature. The organic layer was separated and washed with water andevaporated to give 35.35 gm of (+)-(S)—Clopidogrel base as an oil.

Example 6 (S)(+) Clopidogrel Base

93.0 gm (0.28 mole) of racemic basemethyl-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetateis charged in 550 ml. mixture of acetone and toluene. 73.8 gm (0.31mole) levo-camphor-10-sulphonic acid is added to the solution. The clearsolution is stirred overnight at 30±2° c. The reaction mass is cooled to−2 to 3° c. The crystals obtained is filtered and washed with acetoneand dried under reduced pressure. The yield obtained is 80% on the basisof the starting racemate charged. The crystals have [[a]D20+24.49(c=1.89%, methanol); HPLC(AGP(R) column) assay=99.285%]. The camphorsulphonate salt was further cleaved to obtain (S)(+) clopidogrel base asin example 5.

Example 7

Clopidogrel base (5.79 kg) was dissolved in methyl propyl ketone (37liter) at room temperature. This mixture was cooled to −10° C. andconcentrated sulphuric acid (96%, density=1.83) was added (1.02 liter)maintaining temperature −10° to 0° C. while addition. The reaction masswas stirred for 1.0 hour and warmed slowly to 10 to 15° C. in 30 to 45minute. The formed crystals were stirred for 7 hours. The reaction masstemperature was further raised to 28 to 30° C. and maintained for 8.0hours. The solid obtained was filtered under suction and washed withmethyl propyl ketone, and dried in oven at 48° C. for 3 hour. The solidafter drying weighed 6.82 kg (90%) was Form I clopidogrel hydrogensulphate (PXRD pattern incorporated: FIG. 1)

Example 8

Clopidogrel base (5.79 kg) was dissolved in methyl isopropyl ketone (37liter) at room temperature. This mixture was cooled to −10° C. andconcentrated sulphuric acid (96%, density=1.83) was added (1.02 liter)maintaining temperature −10° to 0° C. while addition. The reaction masswas stirred for 1.0 hour and warmed slowly to 10 to 15° C. in 30 to 45minutes. The formed crystals were stirred for 7 hour. The reaction masstemperature was further raised to 28 to 30° C. and maintained for 8.0hour. The solid obtained was filtered under suction and washed withmethyl isopropyl ketone, and dried in oven at 48° C. for 3 hour. Thesolid after drying weighed 6.82 kg (90%) was Form I clopidogrel hydrogensulphate (PXRD pattern is identical with FIG. 1).

Example 9

Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) atroom temperature. This mixture was cooled to 18° C. and concentratedsulphuric acid (96%, density=1.83) was added (1.02 liter) maintainingtemperature 18° to 20° C. while addition. The reaction mass was stirredfor 30 minutes and warmed slowly to 28° to 30° C. in 30 to 40 minute.The formed crystals were stirred for 8 hours. The solid obtained wasfiltered under suction and washed with ethyl acetate, and dried in ovenat 40° C. for 3 hours. The solid after drying weighed 6.7 kg (88%) wasForm I clopidogrel hydrogen sulphate (PXRD pattern is identical withFIG. 1).

Example 10

Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) atroom temperature. This mixture was heated to 45° C. and concentratedsulphuric acid (96%, density=1.83) was added (1.02 liter). The reactionmass was stirred for 30 minutes at 45° to 50° C. The formed crystalswere cooled to 30° C. in one hour and stirred for 4 hours. The solidobtained was filtered under suction and washed with ethyl acetate, anddried in oven at 48° C. for 3 hours. The solid after drying weighed 6.5kg (86%) and identified as pure clopidogrel hydrogen sulphate Form II(PXRD pattern incorporated: FIG. 2).

Example 11

Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) atroom temperature. This mixture was cooled to 20° C. and concentratedsulphuric acid (98%, density=1.84) was added (1.02 liter). Thetemperature rose to 28° C. while addition and the reaction mass wasstirred for 10 hour at 28° to 30° C. The solid obtained was filteredunder suction and washed with ethyl acetate, and dried in oven at 40° C.for 3 hour. The solid after drying weighed 6.8 kg (89.6%) and identifiedas pure clopidogrel hydrogen sulphate Form I (PXRD pattern is identicalwith FIG. 1).

Example 12

Clopidogrel base (7.25 kg) was dissolved in isopropyl alcohol (62.5liter) at room temperature. This mixture was maintained at 28° to 30° C.and concentrated sulphuric acid solution in isopropyl alcohol (preparedby mixing 1.14 liter concentrated sulphuric acid and 43.5 literisopropyl alcohol) was added. The reaction mass was stirred for 12 hourat 28° to 30° C. The solid obtained was filtered under suction andwashed with ethyl acetate, and dried in oven at 48° C. for 3 hours. Thesolid after drying weighed 7.6 kg (80%) and identified as pureclopidogrel hydrogen sulphate Form II (PXRD pattern as in example 4).

Example 13

Clopidogrel base (5.79 kg) was dissolved in tetrahydrofuran (30 liter)at room temperature. This mixture was cooled to 10° to 15° C. andconcentrated sulphuric acid (80%) solution 1.4 liter was added whilemaintaining the temperature under cooling. The reaction mass was stirredfor 8 hour at 13° to 15° C. The solid obtained was filtered undersuction and washed with tetrahydrofuran, and dried in oven at 48° C. for3 hour. The solid after drying weighed 5.9 kg (78%) and identified aspure clopidogrel hydrogen sulphate Form II (PXRD pattern as in example4).

Example 14

Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) atroom temperature. This mixture was cooled to 5° C. and concentratedsulphuric acid (98%, density=1.84) was added (1.02 liter) whilemaintaining the temperature at 5° to 10° C. and the reaction mass wasstirred for 3 hour at 10° to 15° C. and maintained for 10 to 12 hour at24° C. The solid obtained was filtered under suction and washed withethyl acetate, and dried in oven at 48° C. for 3 hour. The solid afterdrying weighed 6.9 kg (90%) and identified as pure clopidogrel hydrogensulphate Form II (PXRD pattern was identical as in example 4).

Example 15

Clopidogrel base (5.79 kg) was dissolved in ethyl acetate (30 liter) atroom temperature. This mixture was cooled to 10° C. and concentratedsulphuric acid (98%, density=1.84) was added (1.02 liter) whilemaintaining the temperature at 10° to 15° C. and the reaction mass wasstirred for 10 hour at 15° C. The solid obtained was filtered undersuction and washed with ethyl acetate, and dried in oven at 48° C. for 3hours. The solid after drying weighed 6.7 kg (89.6%) and identified aspure clopidogrel hydrogen sulphate Form II (PXRD pattern was identicalas in example 4).

It will be evident to those skilled in the art that the invention is notlimited to the details of the foregoing illustrative examples and thatthe present invention may be embodied in other specific forms withoutdeparting from the essential attributes thereof, and it is thereforedesired that the present embodiments and examples be considered in allrespects as illustrative and not restrictive, reference being made tothe appended claims, rather than to the foregoing description, and allchanges which come within the meaning and range of equivalency of theclaims are therefore intended to be embraced therein.

1-31. (canceled)
 32. Crystalline Form I of (+)-(S)-clopidogrel hydrogensulphate without detectable contamination of Form II crystals. 33.Crystalline Form I of (+)-(S)-clopidogrel hydrogen sulphate according toclaim 32, wherein the powder x-ray diffraction pattern contains no peaksof Form II in the region of 12.2-13.5±0.2 degrees 2θ angle. 34.Crystalline Form I of (+)-(S)-clopidogrel hydrogen sulphate according toclaim 32, wherein the powder x-ray diffraction pattern shows no peaks inthe region of 12.2-13.5±0.2 degrees 2θ angle after storage for a periodof at least one year.
 35. (+)-(S)-clopidogrel hydrogen sulphateaccording to claim 32, characterized by the x-ray diffraction pattern asshown in FIG.
 1. 36. A pharmaceutical composition comprising(+)-(S)-clopidogrel hydrogen sulphate according to claim
 32. 37. Apharmaceutical composition comprising crystalline Form I of(+)-(S)-clopidogrel hydrogen sulphate characterized by powder x-raydiffraction pattern containing no peaks of Form II in the region of12.2-13.5±0.2 degrees 2θ angle
 38. A process for making Form I crystalsof (+)-(S)-clopidogrel hydrogen sulphate of Formula IB,

said process comprising: i) dissolving methyl(+)-(S)-[alpha]-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate((+)-(S)-clopidogrel base) in ethyl acetate; ii) cooling to atemperature of 18 to 20° C.; iii) mixing said cooled solution withconcentrated sulphuric acid in which the temperature not exceeding 30°C.; iv) maintaining the salt mixture at 28 to 30° C. for 7 to 10 hoursto effect precipitation of (+)-(S)-clopidogrel hydrogen sulphate in FormI; and v) recovering said crystals of Form I.
 39. The process of claim38, wherein step iii) is carried out while maintaining the temperatureat 18 to 24° C.
 40. The process of claim 38, wherein the strength ofsaid sulphuric acid is about 95 to 98%.
 41. The process of claim 38,wherein the molar ratio of sulphuric acid used is 1.02 to 1.1 relativeto (+)-(S)-clopidogrel base.
 42. The process as claimed in any one ofthe claim 38, wherein the Form I crystals are recovered withoutdetectable contamination by Form II crystals.
 43. Crystalline Form I ofclopidogrel hydrogen sulphate prepared according to any one of the claim38, characterized by a powder x-ray diffraction pattern containing nopeaks in the region of 12.2-13.5±0.2 degrees 2θ angle.
 44. The processaccording to any one of the claim 38, wherein the recovered Form Icrystals are characterized by a powder x-ray diffraction pattern asshown in FIG.
 1. 45. A process for making clopidogrel of Formula Icomprising

i) reacting 2-(2-thieno)ethylamine of Formula IV with paraformaldehydeto form 4,5,6,7-tetrahydrothieno(3,2-c)pyridine of Formula II, whereinthe step takes place in a single vessel without isolation of2-(2-thienyl)ethyl formimine; and ii) reacting the compound of FormulaII with a halobenzene derivative of Formula III, wherein X═Cl or Br, inpresence of a base in a solvent selected from dichloroethane or water ora mixture of water and hydrocarbon/chlorinated hydrocarbon solvents toobtain clopidogrel and isolating said clopidogrel as free base or itssalt.
 46. The process of claim 45, wherein the step i) is performed in asolvent selected from aliphatic, aromatic hydrocarbons and chlorinatedhydrocarbons.
 47. The process of claim 46, wherein the solvent isdichloroethane.
 48. The process of claim 45, wherein 2-(2-thienyl)ethylformimine is formed in-situ by effective removal of water at refluxtemperature and cyclized in presence of anhydrous hydrochloric acid. 49.The process of claim 45, wherein said4,5,6,7-tetrahydrothieno(3,2-c)pyridine is formed at a temperatureranging from about 60 to 90° C.
 50. The process of claim 45, whereinstep ii) is carried out in dichloroethane.
 51. The process of claim 45,wherein the base is selected from trialkyl amines.
 52. The process ofclaim 45, wherein the base is triethyl amine.
 53. The process of inclaim 45, wherein step ii) takes place at a temperature of 50 to 80° C.54. The process of claim 45, wherein the clopidogrel is prepared in asingle-pot procedure without isolation of intermediates4,5,6,7-tetrahydrothieno(3,2-c)pyridine or its salts.
 55. The process ofclaim 45, wherein step i) takes place in the presence of an acidcatalyst.
 56. The process of claim 55, wherein the acid catalyst ishydrogenchloride.
 57. A process for preparation of clopidogrel ofFormula I

comprising the step of reacting 4,5,6,7-tetrahydrothieno(3,2-c)pyridineof formula II

or its salt with a halobenzene derivative of Formula III

in presence of a base in a solvent, wherein the solvent is chlorinatedhydrocarbon, water or a mixture of water and hydrocarbon solventsselected from aliphatic, aromatic and chlorinated hydrocarbons.
 58. Theprocess of claim 57, wherein the solvent is a combination ofdichloroethane and water.
 59. The process of claim 57, wherein the baseis sodium carbonate or potassium carbonate.
 60. The process of claim 57,wherein reaction is performed at a temperature of 20 to 40° C.
 61. Theprocess of claim 57, wherein the compound of Formula III ismethyl-1-bromo-(2-chlorophenyl)acetate.
 62. The process of claim 57,further comprising the steps of treating said clopidogrel of Formula Iwith levo-rotatory camphor sulphonic acid in a solvent system of polarand apolar/weakly polar solvents; and obtaining substantially puredextrorotatory clopidogrel of Formula IA


63. The process of claim 62, wherein the solvent system is acetone anddichloromethane; acetone and toluene; or acetone and cyclohexane
 64. Theprocess of claim 63, wherein the combination solvent is acetone anddichloromethane.
 65. The process of claim 64, wherein the ratio ofacetone and dichloromethane is 10:1.
 66. A process for preparation ofdextrorotatory clopidogrel or its salt comprising the step of resolvingracemic clopidogrel with levo-rotatory camphor sulphonic acid in asolvent system of polar and apolar/weakly polar solvents to obtainsubstantially pure dextrorotatory clopidogrel of Formula IA.
 67. Theprocess of claim 66, wherein the solvent system isacetone:dichloromethane, acetone:toluene, or acetone: cyclohexane. 68.The process of claim 67, wherein the combination solvent isacetone:dichloromethane.